WO2017098254A1 - Modulators of kv3 channels to treat pain - Google Patents

Modulators of kv3 channels to treat pain Download PDF

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Publication number
WO2017098254A1
WO2017098254A1 PCT/GB2016/053879 GB2016053879W WO2017098254A1 WO 2017098254 A1 WO2017098254 A1 WO 2017098254A1 GB 2016053879 W GB2016053879 W GB 2016053879W WO 2017098254 A1 WO2017098254 A1 WO 2017098254A1
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alkyl
modulator
oxy
methyl
pain
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PCT/GB2016/053879
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English (en)
French (fr)
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Charles Large
Giuseppe Alvaro
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Autifony Therapeutics Limited
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Priority to EA201891377A priority Critical patent/EA038059B1/ru
Priority to CN202410102663.8A priority patent/CN118267386A/zh
Priority to KR1020187017088A priority patent/KR20180097549A/ko
Priority to CA3005302A priority patent/CA3005302A1/en
Priority to BR112018011700-5A priority patent/BR112018011700B1/pt
Priority to JP2018529633A priority patent/JP7149847B2/ja
Priority to SG11201804123VA priority patent/SG11201804123VA/en
Priority to FIEP16813020.1T priority patent/FI3386506T3/fi
Priority to ES16813020T priority patent/ES2974902T3/es
Priority to PL16813020.1T priority patent/PL3386506T3/pl
Application filed by Autifony Therapeutics Limited filed Critical Autifony Therapeutics Limited
Priority to EP16813020.1A priority patent/EP3386506B1/en
Priority to CN201680072639.8A priority patent/CN108472288B/zh
Priority to DK16813020.1T priority patent/DK3386506T3/da
Priority to AU2016367239A priority patent/AU2016367239B2/en
Priority to US16/060,714 priority patent/US11147813B2/en
Priority to HRP20240497TT priority patent/HRP20240497T1/hr
Priority to MX2018007074A priority patent/MX2018007074A/es
Publication of WO2017098254A1 publication Critical patent/WO2017098254A1/en
Priority to IL259717A priority patent/IL259717B/en
Priority to US17/472,493 priority patent/US11944623B2/en
Priority to JP2022106247A priority patent/JP2022141699A/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • This invention relates to compounds and pharmaceutical compositions containing such compounds for use in the prophylaxis or treatment of pain, and to related methods and uses.
  • the Kv3 voltage-gated potassium channel family includes four members, Kv3.1, Kv3.2, Kv3.3, and Kv3.4. Genes for each of these subtypes can generate multiple isoforms by alternative splicing, producing versions with different C-terminal domains. Thirteen isoforms have been identified in mammals to date, but the currents expressed by these variants appear similar (Rudy et al., 2001). Kv3 channels are activated by depolarisation of the plasma membrane to voltages more positive than -20mV; furthermore, the channels deactivate rapidly upon repolarisation of the membrane. These biophysical properties ensure that the channels open towards the peak of the depolarising phase of the neuronal action potential to initiate repolarisation.
  • Kv3.1-Kv3.3 subtypes are predominant in the CNS, whereas Kv3.4 channels are found predominantly in skeletal muscle and sympathetic neurons (Weiser et al., 1994).
  • Kv3.1-Kv3.3 channel subtypes are differentially expressed by sub-classes of interneurons in cortical and hippocampal brain areas (e.g.
  • Kv3 channels are important determinants of the function of the cerebellum, a region of the brain important for motor control (Joho et al., 2009). Characterisation of mice in which one or more of the Kv3 subtypes has been deleted shows that the absence of Kv3.1 gives rise to increased locomotor activity, altered electroencephalographic activity, and a fragmented sleep pattern (Joho et al., 1999). The deletion of Kv3.2 leads to a reduction in seizure threshold and altered cortical electroencephalographic activity (Lau et al., 2000). Deletion of Kv3.3 is associated with mild ataxia and motor deficits (McMahon et al., 2004).
  • Double deletion of Kv3.1 and Kv3.3 gives rise to a severe phenotype characterised by spontaneous seizures, ataxia, and an increased sensitivity to the effects of ethanol (Espinosa et al., 2001; Espinosa et al., 2008).
  • TAA Tetraethylammonium
  • BDS blood- depressing substance
  • Patent applications WO2011/069951, WO2012/076877, WO2012/168710, WO2013/175215, WO2013/083994 and WO2013/182850 disclose compounds which are modulators of Kv3 channels, specifically Kv3.1, Kv3.2 and Kv3.3. Use of such compounds in certain diseases and disorders requiring modulation of Kv3 channels are disclosed in patent applications
  • pain can be grouped in to acute pain and chronic pain.
  • Acute pain is defined as pain that is self-limited and generally requires treatment for no more than up to a few weeks, for example postoperative or acute musculoskeletal pain, such as fractures (US Food and Drug Administration, 2014).
  • Chronic pain can be defined either as pain persisting for longer than 1 month beyond resolution of the initial trauma, or pain persisting beyond three months. There is often no clear cause of chronic pain, and a multitude of other health problems such as fatigue, depression, insomnia, mood changes and reduction in movement, often accompany chronic pain.
  • Chronic pain can be sub-divided in to the following groups: neuropathic pain, chronic musculoskeletal pain and miscellaneous chronic pain.
  • Neuropathic pain usually accompanies tissue injury and is initiated or caused by damage to the nervous system (peripheral nervous system and/or central nervous system), such as amputation, stroke, diabetes, or multiple sclerosis.
  • Chronic musculoskeletal pain can be a symptom of diseases such as osteoarthritis and chronic lower back pain and can occur following damage to muscle tissue as well as trauma to an area, for example, fractures, sprains and dislocation.
  • Miscellaneous chronic pain encompasses all other types of long term pain and includes non-neuropathic pain conditions such as cancer pain and fibromyalgia as well as headaches and tendinitis.
  • Voltage-gated ion channels have been important targets for the management of specific pain indications, in particular neuropathic pain states. Furthermore, genetic mutations in specific ion channels have been linked to some chronic pain disorders (Bennett et al., 2014). Examples of voltage-gated ion channels that are being explored as pharmaceutical targets include: Sodium channels (in particular NaV1.7) - Sun et al., 2014; Dib-Hajj et al., 2013
  • Drugs targeting hyperexcitability such as sodium channel blockers (e.g. CNV1014802, lamotrigine, carbamazepine, and local anaesthetics), Kv7 positive modulators (e.g. flupertine and retigabine), and N-type calcium channel modulators (e.g. gabapentin, which interacts with the ⁇ 2 ⁇ subunit of the N-type calcium channel, and ziconitide, derived from a cone snail toxin) show efficacy in models of inflammatory and/or neuropathic pain.
  • sodium channel blockers e.g. CNV1014802, lamotrigine, carbamazepine, and local anaesthetics
  • Kv7 positive modulators e.g. flupertine and retigabine
  • N-type calcium channel modulators e.g. gabapentin, which interacts with the ⁇ 2 ⁇ subunit of the N-type calcium channel, and ziconitide, derived from a cone snail toxin
  • a further target of interest is SLACK.
  • Preclinical rationale supports good potential efficacy (Lu et al., 2015), although to date, there is a lack of selective compounds which makes it difficult to determine which pain states might be most receptive. Improving the pharmacological management of pain is focused on mechanisms that can deliver good efficacy with a reduced side-effect burden, reduced tolerance or tachyphylaxis, and reduced abuse liability and/or risk of dependence.
  • Kv3.4 channels have become a target of interest for the treatment of chronic pain.
  • Kv3.4 channels are expressed on neurons of the dorsal root ganglia (Ritter et al., 2012; Chien et al., 2007), where they are predominantly expressed on sensory C-fibres (Chien et al., 2007).
  • Kv3 channels are also expressed by specific subsets of neurons in the spinal cord. Specifically, Kv3.1b (Deuchars et al., 2001; Brooke et al., 2002), Kv3.3 (Brooke et al., 2006), and Kv3.4 subunits (Brooke et al., 2004) have been identified in rodent spinal cord, although not always in association with circuits involved with sensory processing. Recent animal model data suggest a down-regulation of Kv3.4 channel surface expression in DRG neurons following spinal cord injury associated with hypersensitivity to painful stimuli (Ritter et al., 2015).
  • modulation of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels is linked to the processing of pain and pain control. Therefore, modulation of Kv3.1 and/or Kv3.2 and/or Kv3.3 represents a new approach for the prophylaxis or treatment of pain. Summary of the invention
  • the present invention provides a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels (referred to herein as "Kv3.1/Kv3.2/Kv3.3" or "Kv3.1 and/or Kv3.2 and/or Kv3.3") for use in the prophylaxis or treatment of pain.
  • the present invention further provides the use of a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels in the manufacture of a medicament for the prophylaxis or treatment of pain.
  • the present invention also provides a method of prophylaxis or treatment of pain by administering a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels.
  • the modulator is a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof:
  • Ri is H, Ci- 4 alkyl, halo, haloCi- 4 alkyl, CN, Ci- 4 alkoxy, or haloCi- 4 alkoxy;
  • R2 is H, Ci- 4 alkyl, C3-5 spiro carbocyclyl, haloCi- 4 alkyl or halo;
  • R3 is H, Ci- 4 alkyl, haloCi- 4 alkyl, halo; or R3 is absent;
  • Ri3 is H, Ci- 4 alkyl, haloCi- 4 alkyl, halo; or R13 is absent;
  • Ri 4 is H, Ci- 4 alkyl, haloCi- 4 alkyl, halo; or Ri 4 is absent;
  • A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;
  • R 2 and R3 may be attached to the same or a different ring atom;
  • R 2 may be attached to a fused ring atom; and wherein R13 and Ri 4 may be attached to the same or a different ring atom;
  • Ri6 is halo, Ci-4 alkyl, Ci- 4 alkoxy, halo-Ci- 4 alkyl, halo-Ci- 4 alkoxy, or CN;
  • Ri7 is H, halo, cyano, Ci- 4 alkyl or Ci -4 alkoxy; with the proviso that when R17 is H,
  • Ri6 is not in the para position
  • R22 is H, CI, F or Ci- 4 alkyl
  • R23 is H, Ci- 4 alkyl, CI, CF 3 , 0-Ci- 4 alkyl, OCF 3 or N(CH 3 ) 2 ;
  • R 24 is H, CI, F, Ci- 4 alkyl, 0-Ci- 4 alkyl, CN, OCF 3 or CF 3 ;
  • R25 is H, CI, F, 0-Ci- 4 alkyl or Ci- 4 alkyl
  • R26 is H or Ci- 4 alkyl
  • Ci- 4 alkyl may be substituted by O- with the provisos that:
  • R22 to R26 may be H
  • R 4 when R 4 is H, then R2 3 is methyl or CF 3 and R22, R ⁇ 4 , R25 and R26 are all H;
  • R22, R ⁇ 4 , R25 or R26 when one of R22, R ⁇ 4 , R25 or R26 is F, then at least one of R22 to R26 cannot be H or F;
  • R2 4 when R2 4 is not H, at least one of R22 or R2 3 is not H;
  • X is CH or N
  • Y is CRi 5 or N
  • Ri5 is H or Ci- 4 alkyl
  • R 4 is Ci- 4 alkyl
  • R5 is H or Ci- 4 alkyl
  • R 4 and R5 can be fused to form C 3 - 4 spiro carbocyclyl
  • R 4 is H or Ci- 4 alkyl.
  • the compounds of formula (I) may be used as medicaments, in particular for the prophylaxis or treatment of pain, such as neuropathic or inflammatory pain. Additionally provided is a method of identifying that a compound is of use in the prophylaxis or treatment of pain, said method comprising the step of determining that the compound is a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels.
  • a method for the manufacture of a pain medicament comprising the steps: (i) determining that a compound is a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels and (ii) preparing a medicament comprising the compound.
  • the pain medicament may be for the prophylaxis or treatment of pain.
  • Figure 1 shows the effect of Compound 1 on paw withdrawal thresholds under mechanical pressure in a neuropathic pain model (Study 1): ipsilateral paw (Fig. la); contralateral paw (Fig. lb); and percentage reversals (Fig.lc).
  • Figure 2 shows the effect of Compound 1 on paw withdrawal thresholds to a cold stimulus (10°C) in a neuropathic pain model (Study 1): ipsilateral paw (Fig.2a); contralateral paw (Fig.2b); and percentage reversals (Fig.2c).
  • Figure 3 shows the effect of Compound 1 on paw withdrawal thresholds under mechanical pressure in a neuropathic pain model (Study 2): ipsilateral paw (Fig.3a); contralateral paw (Fig.3b); and percentage reversals (Fig.3c).
  • Figure 4 shows the effect of Compound 1 on paw withdrawal thresholds to a cold stimulus (10°C) in a neuropathic pain model (Study 2): ipsilateral paw (Fig.4a); contralateral paw (Fig.4b); and percentage reversals (Fig.4c).
  • Figure 5 shows the effect of Compound 1 on paw withdrawal thresholds under mechanical pressure in an inflammatory pain model: ipsilateral paw (Fig.5a); contralateral paw (Fig.5b); and percentage reversals (Fig.5c).
  • Figure 6 shows the effect of Compound 1 on paw withdrawal thresholds to a cold stimulus (10°C) in an inflammatory pain model: ipsilateral paw (Fig.6a); contralateral paw (Fig.6b); and percentage reversals (Fig.6c).
  • Figure 7 shows the effect of Compound 2 on paw withdrawal thresholds under mechanical pressure in a neuropathic pain model (Study 1): ipsilateral paw (Fig.7a); contralateral paw (Fig.7b); and percentage reversals (Fig.7c).
  • Figure 8 shows the effect of Compound 2 on paw withdrawal thresholds to a cold stimulus (10°C) in a neuropathic pain model (Study 1): ipsilateral paw (Fig.8a); contralateral paw (Fig.8b); and percentage reversals (Fig.8c).
  • Figure 9 shows the effect of Compound 2 on paw withdrawal thresholds under mechanical pressure in a neuropathic pain model (Study 2): ipsilateral paw (Fig.9a); contralateral paw (Fig.9b); and percentage reversals (Fig.9c).
  • Figure 10 shows the effect of Compound 2 on paw withdrawal thresholds to a cold stimulus (10°C) in a neuropathic pain model (Study 2): ipsilateral paw (Fig.10a); contralateral paw (Fig.10b); and percentage reversals (Fig.10c).
  • Figure 11 shows the effect of Compound 2 on paw withdrawal thresholds under mechanical pressure in an inflammatory pain model: ipsilateral paw (Fig.11a); contralateral paw (Fig. lib); and percentage reversals (Fig.11c).
  • Figure 12 shows the effect of Compound 2 on paw withdrawal thresholds to a cold stimulus (10°C) in an inflammatory pain model: ipsilateral paw (Fig.12a); contralateral paw (Fig.12b); and percentage reversals (Fig.12c).
  • Figure 13 shows the effect of Compound 3 on paw withdrawal thresholds under mechanical pressure in a neuropathic pain model: ipsilateral paw (Fig.13a); contralateral paw (Fig.13b); and percentage reversals (Fig.13c).
  • Figure 14 shows the effect of Compound 3 on paw withdrawal thresholds to a cold stimulus (10°C) in a neuropathic pain model: ipsilateral paw (Fig.14a); contralateral paw (Fig.14b); and percentage reversals (Fig.14c).
  • Figure 15 shows the effect of Compound 3 on paw withdrawal thresholds under mechanical pressure in an inflammatory pain model: ipsilateral paw (Fig.15a); contralateral paw (Fig.15b); and percentage reversals (Fig.15c).
  • Figure 16 shows the effect of Compound 3 on paw withdrawal thresholds to a cold stimulus (10°C) in an inflammatory pain model: ipsilateral paw (Fig.16a); contralateral paw (Fig.16b); and percentage reversals (Fig.16c).
  • Figure 17 shows the effect of Compound 4 on paw withdrawal thresholds under mechanical pressure in an inflammatory pain model: ipsilateral paw (Fig.17a); contralateral paw (Fig.17b); and percentage reversals (Fig.17c).
  • Figure 18 shows the effect of Compound 4 on paw withdrawal thresholds to a cold stimulus (10°C) in an inflammatory pain model: ipsilateral paw (Fig.18a); contralateral paw (Fig.18b); and percentage reversals (Fig.18c).
  • the present invention provides a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels for use in the prophylaxis or treatment of pain.
  • the present invention further provides the use of a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels in the manufacture of a medicament for the prophylaxis or treatment of pain.
  • the present invention also provides a method of prophylaxis or treatment of pain by administering a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels.
  • the modulator is a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof:
  • Ri is H, Ci- 4 alkyl, halo, haloCi- 4 alkyl, CN, Ci- 4 alkoxy, or haloCi- 4 alkoxy;
  • R2 is H, Ci- 4 alkyl, C3-5 spiro carbocyclyl, haloCi- 4 alkyl or halo;
  • R3 is H, Ci- 4 alkyl, haloCi- 4 alkyl, halo; or R3 is absent;
  • Ri3 is H, Ci- 4 alkyl, haloCi- 4 alkyl, halo; or R13 is absent;
  • Ri 4 is H, Ci- 4 alkyl, haloCi- 4 alkyl, halo; or Ri 4 is absent;
  • A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;
  • R 2 and R3 may be attached to the same or a different ring atom;
  • R 2 may be attached to a fused ring atom; and wherein R13 and Ri 4 may be attached to the same or a different ring atom;
  • Ri6 is halo, Ci-4 alkyl, Ci- 4 alkoxy, halo-Ci- 4 alkyl, halo-Ci- 4 alkoxy, or CN;
  • Ri7 is H, halo, cyano, Ci- 4 alkyl or Ci -4 alkoxy; with the proviso that when R17 is H,
  • Ri6 is not in the para position
  • R 22 is H, CI, F or Ci- 4 alkyl
  • R 23 is H, Ci- 4 alkyl, CI, CF 3 , 0-Ci- 4 alkyl, OCF 3 or N(CH 3 ) 2 ;
  • R24 is H, CI, F, Ci- 4 alkyl, 0-Ci- 4 alkyl, CN, OCF 3 or CF 3 ;
  • R25 is H, CI, F, 0-Ci- 4 alkyl or Ci- 4 alkyl
  • R26 is H or Ci- 4 alkyl
  • Ci- 4 alkyl may be substituted by O-methyl
  • R22 to R26 may be H
  • R 4 when R 4 is H, then R2 3 is methyl or CF 3 and R22, R ⁇ 4 , R25 and R26 are all H;
  • R22, R ⁇ 4 , R25 or R26 when one of R22, R ⁇ 4 , R25 or R26 is F, then at least one of R22 to R26 cannot be H or F;
  • R2 4 when R2 4 is not H, at least one of R22 or R2 3 is not H;
  • X is CH or N
  • Ri5 is H or Ci- 4 alkyl
  • R 4 is Ci- 4 alkyl
  • R5 is H or Ci- 4 alkyl
  • R 4 and R5 can be fused to form C 3 - 4 spiro carbocyclyl
  • R 4 is H or Ci- 4 alkyl.
  • the compounds of formula (I) may be used as medicaments, in particular for the prophylaxis or treatment of pain, such as neuropathic or inflammatory pain.
  • the modulator is a compound of formula (IA):
  • Ri, R 2 , R 3 , Ri 3 , Ri4, A, X, Y, R 4 and R5 are as defined above for compounds for formula (I).
  • the modulator is a compound of formula (I B):
  • Ri, R 2 , R 3 , Ri 3 , Ri 4 , A, X, Y, R 4 and R5 are as defined above for compounds for formula (I).
  • the modulator is a compound of formula (I D):
  • Ri, R 2 , R 3 , Ri 3 , Ri4, A, X, Y and R 4 are as defined above for compounds for formula (I).
  • the modulator is a compound of formula (IF):
  • R22, R 23 , R 24 , R25, R26, X, Y and R 4 are as defined above for compounds for formula (I).
  • Ri is H, Ci- 4 alkyl, halo or haloCi- 4 alkyl. In another embodiment of the invention Ri is H or methyl. In one embodiment of the invention Ri is H. In another embodiment of the invention Ri is Ci- 4 alkyl, in particular methyl.
  • W is group (Wa)
  • W is group (Wb)
  • Ri is H or methyl.
  • W is group (Wb)
  • Ri is positioned at the para position of the phenyl ring, as illustrated below:
  • R 2 is H, Ci- 4 alkyl, C 3 -sspiro carbocyclyl, or haloCi- 4 alkyl.
  • R 2 is Ci- 4 alkyl, in particular methyl, ethyl, isopropyl, tert-butyl or cyclopropyl, especially methyl, ethyl, isopropyl or tert-butyl.
  • R 2 is C 3 - 5spiro carbocyclyl.
  • R 2 is C 3 spiro carbocyclyl.
  • R 2 is C 4 spiro carbocyclyl.
  • R 2 is Csspiro carbocyclyl.
  • R 2 is haloCi- 4 alkyl, in particular trifluoromethyl or 2,2,2-trifluoroethyl.
  • R 2 is halo, in particular fluoro.
  • R 2 is H.
  • R 3 is H, Ci- 4 alkyl, haloCi- 4 alkyl or halo.
  • R 3 is H, Ci- 4 alkyl, or haloCi- 4 alkyl.
  • R 3 is H or Ci- 4 alkyl.
  • R 3 is H.
  • R 3 is Ci- 4 alkyl, in particular methyl, ethyl, isopropyl, tert-butyl or cyclopropyl, especially methyl, ethyl, isopropyl or tert-butyl, such as methyl or ethyl.
  • R 3 is haloCi- 4 alkyl, in particular trifluoromethyl or 2,2,2-trifluoroethyl.
  • R 3 is halo, in particular fluoro.
  • R 3 is absent.
  • R 3 is H, methyl or trifluoromethyl.
  • R 2 may be H, Ci- 4 alkyl, haloCi- 4 alkyl or C 3 -sspiro carbocyclyl and R 3 may be H, Ci- 4 alkyl, or haloCi- 4 alkyl.
  • R 2 may be methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, C 3 -sspiro carbocyclyl, trifluoromethyl or 2,2,2-trifluoroethyl and R 3 may be H, methyl, ethyl or trifluoromethyl.
  • R 3 is H and R 2 is H, methyl, ethyl, isopropyl or C 3 - 4 spiro carbocyclyl.
  • R 3 and R 2 are both fluoro (such as attached to the same ring carbon atom).
  • R 2 is Ci- 4 alkyl and R 3 is H, for example R 2 is methyl, ethyl, tert-butyl or cyclopropyl.
  • R 2 is Ci- 4 alkyl and R 3 is Ci- 4 alkyl, for example R 2 is methyl and R 3 is methyl, R 2 is ethyl and R 3 is ethyl or R 2 is methyl and R 3 is ethyl. In another embodiment of the invention R 2 is trifluoromethyl and R 3 is methyl.
  • R 2 and R 3 are attached to the same ring atom. In an alternative embodiment of the invention R 2 and R 3 are attached to different ring atoms.
  • R13 is H, F or methyl.
  • Ri3 is H.
  • R13 is Ci- 4 alkyl, in particular methyl.
  • R13 is halo, in particular fluoro.
  • R13 is haloCi- 4 alkyl, such as trifluoromethyl.
  • Ri 4 is H, F or methyl. In one embodiment of the invention Ri 4 is H. in another embodiment of the invention Ri 4 is Ci- 4 alkyl, in particular methyl. In a further embodiment of the invention Ri 4 is halo, in particular fluoro. In an additional embodiment of the invention R13 is haloCi- 4 alkyl, such as trifluoromethyl.
  • Ri 4 may be absent. Consequently, in another embodiment of the invention Ri 4 is absent.
  • R13 and Ri 4 are attached to the same ring atom. In an alternative embodiment of the invention R13 and Ri 4 are attached to different ring atoms.
  • R 2 , R3, R13 and Ri 4 are each independently selected from H, Ci- 4 alkyl, haloCi- 4 alkyl and halo, such as H, Ci- 4 alkyl and haloCi- 4 alkyl.
  • R 2 , R3, Ri3 and Ri 4 are each independently selected from H, F, methyl and trifluoromethyl.
  • A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group to form a tricycle when considered together with the phenyl.
  • A is a 5 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, a cyclobutyl group or a cyclopentyl group to form a tricycle when considered together with the phenyl.
  • A is a 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, a cyclobutyl group or a cyclopentyl group to form a tricycle when considered together with the phenyl.
  • A is a 5 membered saturated or unsaturated heterocycle with at least one O atom, which heterocycle is fused with a cyclopropyl group to form a tricycle when considered together with the phenyl.
  • A is a 6 membered saturated or unsaturated heterocycle with at least one O atom, which heterocycle is fused with a cyclopropyl group to form a tricycle when considered together with the phenyl.
  • A is a 5 membered saturated or unsaturated heterocycle with at least one O atom.
  • A is a 6 membered saturated or unsaturated heterocycle with at least one O atom.
  • the ring A contains one heteroatom.
  • the ring A contains two heteroatoms (e.g. two oxygen atoms, one oxygen atom and one nitrogen atom, or one oxygen atom and one sulphur atom), in particular two oxygen atoms or one oxygen atom and one nitrogen atom.
  • A is dihydrofuran, isoxazole, dihydropyran, 1,3-dioxolane, 1,3-oxazine or
  • A is dihydrofuran. In one embodiment of the invention A is dihydropyran. In another embodiment of the invention A is dihydrofuran fused with a cyclopropyl group, a cyclobutyl group or a cyclopentyl group. In another embodiment of the invention A is dihydropyran fused with a cyclopropyl group, a cyclobutyl group or a cyclopentyl group. In a further embodiment the invention A is dihydrofuran fused with a cyclopropyl group. In still further embodiment the invention A is dihydropyran fused with a cyclopropyl group.
  • A is fused with a cyclopropyl group. In another embodiment A is fused with a cyclobutyl group. In a further embodiment of the invention A is fused with a cyclopentyl group. In one embodiment of the invention A is not fused with a cyclopropyl group, a cyclobutyl group or a cyclopentyl group.
  • A is dihydrofuran, dihydropyran, furan, pyran, oxazole, isoxazole, oxazine, dioxine or 1,3-dioxalane. In another embodiment A is dihydrofuran, dihydropyran or 1,3-dioxalane.
  • n denotes a portion of the phenyl ring to which ring A is fused.
  • A contains a 5 membered heterocycle containing one oxygen atom
  • the heterocycle is dihydrofuran.
  • A is a 5 membered heterocycle containing one oxygen atom
  • the oxygen atom is located at the benzylic position relative to the phenyl ring.
  • W is group (Wa)
  • A is a 5 membered heterocycle containing one heteroatom, wherein the oxygen atom is located at the benzylic or para position relative to the phenyl ring.
  • W is group (Wb)
  • A is a 5 membered heterocycle containing one heteroatom, wherein the oxygen atom is located at the benzylic or meta position relative to the phenyl ring.
  • group (Wa) is:
  • group (Wa) is:
  • group (Wb) is:
  • (Wb) is:
  • group (Wb) is:
  • A contains a 6 membered heterocycle containing one oxygen atom
  • the heterocycle is dihydropyran.
  • W is group (Wa)
  • A is a 6 membered heterocycle containing one oxygen atom, wherein the oxygen atom is located at the para position relative to the phenyl ring.
  • W is group (Wb)
  • A contains a 6 membered heterocycle containing one oxygen atom, wherein the oxygen atom is located at the meta position relative to the phenyl ring.
  • group (Wa) is:
  • group (Wa) is:
  • group (Wb) is:
  • group (Wb) is:
  • group (Wb) is:
  • A is:
  • W is group (Wa), in a further embodiment of the invention, A is selected from the group consisting of:
  • m and p denote the meta and para positions, respectively, of ring A relative to the phenyl ring.
  • m and o denote the meta and ortho positions, respectively, of ring A relative to the phenyl ring.
  • m and o denote the meta and ortho positions, respectively, of ring A relative to the phenyl ring.
  • W is the group (Wc):
  • I n one embodiment of the invention Ri6 is Ci- 4 alkoxy. I n another embodiment of the invention Ri6 is methoxy. I n one embodiment of the invention Ri6 is Ci- 4 alkyl. I n another embodiment of the invention Ri6 is methyl. I n a further embodiment of the invention Ri6 is ethyl. I n a yet further embodiment of the invention Ri6 is propyl. I n a yet further embodiment of the invention Ri6 is butyl. I n one embodiment of the invention Ri6 is halo. I n another embodiment of the invention Ri6 is chloro. In a further embodiment of the invention Ri6 is fluoro. In one embodiment of the invention Ri6 is halo-Ci- 4 alkoxy.
  • I n another embodiment of the invention Ri6 is trifluoromethoxy.
  • I n one embodiment of the invention Ri6 is halo-Ci- 4 alkyl.
  • I n another embodiment of the invention Ri6 is trifluoromethyl.
  • I n one embodiment of the invention Ri6 is cyano.
  • R17 is H. I n one embodiment of the invention R17 is Ci- 4 alkyl. I n another embodiment of the invention R17 is methyl. I n one embodiment of the invention R17 is halo. In another embodiment of the invention, R17 is chloro. I n a further embodiment of the invention R17 is fluoro. I n one embodiment of the invention R17 is Ci- 4 alkyl. I n one embodiment of the invention R17 is cyano.
  • I n one embodiment of the invention Ri6 is Ci- 4 alkyl, Ci- 4 alkoxy, or halo-Ci- 4 alkoxy; R17 is H, cyano or alkyl; X is N, Y is N or CR15, R 4 is Ci- 4 alkyl, and R5 is Ci- 4 alkyl or H .
  • I n one embodiment of the invention Ri6 is propyl, butyl, methoxy, propoxy, or trifluoromethoxy; R17 is H, cyano or methyl; X is N, Y is N or CR15, R 4 is ethyl, and R5 is methyl or H.
  • one of Ri6 and R17 is in the para position and the remaining Ri6 or R17 is in the meta position.
  • one of Ri6 and R17 is in the para position and the remaining Ri6 or R17 is in the ortho position.
  • Ri6 is Ci- 4 alkoxy and R17 is Ci- 4 alkyl.
  • Ri6 is methoxy and R17 is methyl.
  • Ri6 is Ci- 4 alkoxy in the meta position and R17 is Ci- 4 alkyl in the para position.
  • Ri6 is methoxy in the meta position, R17 is methyl in the para position, R 4 is Ci- 4 alkyl, R5 is H, R 4 is in the R configuration.
  • Ri6 is methoxy in the meta position, R17 is methyl in the para position, X is N, Y is CH, R 4 is Ci- 4 alkyl, R5 is H and the absolute configuration of the stereogenic centre is R.
  • Ri6 is methoxy in the meta position, R17 is methyl in the para position, X is N, Y is CH, R 4 is ethyl, R5 is H and the absolute configuration of the stereogenic centre is R.
  • W is the group (Wd):
  • R22, R25 and R26 are H.
  • R23 is Ci- 4 alkyl, CI, CF3, 0-Ci- 4 alkyl, OCF3 or N(CH 3 )2, such as Ci-2alkyl, CF 3 , 0-Ci-2alkyl or OCF 3 , in particular OCF 3 and R2 4 is H, CI, F, Ci- 4 alkyl, 0-Ci- 4 alkyl, CN, OCF 3 , such as F, Ci-2alkyl, CF 3 , O-Ci- 2alkyl or OCF 3 , in particular F or methyl and R22, R25 and R26 are H.
  • W is group (Wd)
  • R22 to R26 are H and one of R22 to R26, in particular R22 or R2 3 , is other than H.
  • R22 is other than H, suitably it is methyl.
  • R2 3 is other than H, suitably it is OCF 3 .
  • R 4 is Ci- 4 alkyl.
  • R 4 is methyl, ethyl, isopropyl or t-butyl.
  • R 4 is methyl.
  • R 4 is ethyl.
  • R 4 is propyl, such as isopropyl.
  • R 4 is butyl, such as t- butyl.
  • R5 is H or Ci- 4 alkyl.
  • R5 is H.
  • R 4 is methyl, ethyl, isopropyl or t-butyl.
  • R 4 is methyl.
  • R 4 is ethyl.
  • R 4 is propyl, such as isopropyl.
  • R 4 is butyl, such as t-butyl. I n one embodiment of the invention R 4 and R5 together form a C 3 spiro carbocycle. In a second embodiment of the invention R 4 and R5 together form a C 4 spiro carbocycle.
  • R 4 is methyl and R5 is methyl.
  • R 4 is ethyl and R5 is methyl.
  • R 4 is ethyl and R5 is ethyl.
  • R 4 is ethyl and R5 is H.
  • R 4 and R5 have the stereochemical arrangement
  • R 4 is H.
  • I n a further embodiment of the invention R 4 is Ci- 4 alkyl, in particular methyl, ethyl, isopropyl, tert-butyl or cyclopropyl.
  • I n one embodiment of the invention R 4 is methyl.
  • I n another embodiment of the invention R 4 is ethyl.
  • one embodiment of the invention X is CH. In another embodiment of the invention X is N.
  • I n one embodiment of the invention Y is CR15.
  • I n another embodiment of the invention Y is N
  • I n a further embodiment of the invention Y is CR15, wherein R15 is H.
  • I n a still further embodiment of the invention Y is CR15, wherein R15 is Ci- 4 alkyl, in particular methyl.
  • I n one embodiment of the invention X is CH and Y is CR15, wherein R15 is H.
  • I n another embodiment of the invention X is N and Y is CR15, wherein R15 is H.
  • I n a further embodiment of the invention X is N and Y is CR15, wherein R15 is methyl.
  • I n a further embodiment of the invention X is CH a nd Y is CR15, wherein R15 is methyl.
  • I n a still further embodiment of the invention X is N and Y is N.
  • one embodiment of the invention provides a compound of formula (I Fa):
  • R 4 is CH 3 or H
  • R22 is H, CI, F or Ci- 4 alkyl
  • R23 is H, Ci- 4 alkyl, CI, CF 3 , 0-Ci- 4 alkyl, OCF 3 or N(CH 3 ) 2 ;
  • R 24 is H, CI, F, Ci- 4 alkyl, 0-Ci- 4 alkyl, CN, OCF 3 or CF 3 ;
  • R25 is H, CI, F, 0-Ci- 4 alkyl or Ci- 4 alkyl
  • R 2 6 is H or Ci- 4 alkyl
  • Ci- 4 alkyl may be substituted by O-methyl
  • R 22 to R 2 6 may be H
  • R 23 is methyl or CF 3 and R 22 , R 24 , R 2 5 and R 2 6 are all H;
  • R 22 , R 24 , R 2 5 or R 2 6 when one of R 22 , R 24 , R 2 5 or R 2 6 is F, then R 22 to R 2 6 cannot be H or F;
  • R 24 when R 24 is not H, at least one of R 22 or R 23 is not H;
  • R 22 is Ci- 4 alkyl.
  • I n another embodiment R 22 is methyl.
  • I n a further embodiment R 22 is ethyl.
  • I n a yet further embodiment R 22 is propyl.
  • I n one embodiment of the compounds of formu R23 is H.
  • I n one embodiment of the compounds of formu R23 is Ci-4 alkyl. I n another embodiment of the compounds of formu R23 is Ci-4 alkyl. I n another embodiment of the compounds of formu R23 is Ci-4 alkyl. I n another embodiment of the compounds of formu R23 is Ci-4 alkyl. I n another embodiment of the compounds of formu R23 is Ci-4 alkyl. I n another embodiment of the compounds of formu R23 is Ci-4 alkyl. I n another
  • embodiment of the compounds of formula (IFa) 23 is methyl.
  • I n one embodiment of the compounds of formu R23 is chloro.
  • I n one embodiment of the compounds of formu R23 is methoxy. I n another
  • I n one embodiment of the compounds of formu R23 is trifluoromethyl.
  • I n one embodiment of the compounds of formu R23 is N(CH 3 ) 2 .
  • I n one embodiment of the compounds of formu R 24 is H.
  • I n one embodiment of the compounds of formu R2 4 is methyl.
  • I n one embodiment of the compounds of formu R2 4 is chloro.
  • I n one embodiment of the compounds of formu R2 4 is fluoro.
  • I n one embodiment of the compounds of formu R25 is H.
  • I n one embodiment of the compounds of formu R25 is chloro.
  • I n one embodiment of the compounds of formu R25 is fluoro.
  • I n one embodiment of the compounds of formu R26 is H.
  • one embodiment of the invention provides a compound of formula (I Fb):
  • R 4 is H or Me
  • R23 is C 3 -C 4 alkyl or OC2-C 4 alkyl and R22 is H,
  • R22 and R2 3 are both methyl
  • Ri5 is H or methyl
  • R 4 is H.
  • R 4 is methyl
  • R22 is H.
  • R22 is methyl
  • R2 3 is C 3 -C 4 alkyl.
  • R23 is propyl.
  • R2 3 is methyl
  • R2 3 is OC2-C 4 alkyl.
  • R23 is ethoxy.
  • R2 4 is H.
  • R25 is H.
  • R26 is H.
  • R15 is H.
  • R15 is methyl.
  • References to "formula (I)" should also be construed as also referring to formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), formula (IF), formula (IFa) and formula (IFb) as appropriate to the circumstances.
  • the compound of formula (I) may contain a W group corresponding to one of the following phenol groups:
  • the compound of formula (I) contains a (Wa) group corresponding to one of the following phenol groups:
  • the compound of formula (I) contains a (Wb) group corresponding to one of the following phenol groups:
  • the compound of formula (I) may contain a (Wb) group corresponding to one of the following phenol groups:
  • the compound of formula (I) is selected from: 3-[2-[(3,3-dimethyl-lH-isobenzofuran-5-yl)oxy] pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2,4- dione;
  • the compound of formula (I) is selected from: (5R)-3-[4-(l,3-dihydro-2-benzofuran-4-yloxy)phenyl]-5-methyl-2,4-imidazolidinedione;
  • the compound of formula (I) is not a pharmaceutically acceptable salt (or not any salt).
  • the compound of formula (I) is not a solvate.
  • the compound of formula (I) is not a derivative.
  • enantiomer 1, enantiomer 2, diastereomer 1 and diastereomer 2 refer to the particular enantiomer or disasteriomers named accordingly and described in the original disclosures of these compounds (see WO2011/069951, WO2012/076877, WO2012/168710, WO2013/175215, WO2013/083994 and WO2013/182850, which are incorporated herein by reference for the purposes of providing compounds of use in the present invention).
  • any one feature of the compounds of the invention may be combined with any embodiment of another feature of compounds of the invention to create a further embodiment.
  • the term 'halo' or 'halogen' as used herein, refers to a fluorine, chlorine, bromine or iodine atom. Particular examples of halo are fluorine and chlorine, especially fluorine.
  • the alkyl group may be straight chain, branched, cyclic, or a combination thereof.
  • Examples of Ci- 4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, cyclopropyl and cyclobutyl.
  • Ci- 4 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
  • An example of Ci- 4 alkoxy is methoxy.
  • the term 'haloCi- 4 alkyl' as used herein, includes straight chain, branched chain or cyclic alkyl groups containing 1 to 4 carbon atoms substituted by one or more halo atoms, for example fluoromethyl, difluoromethyl and trifluoromethyl.
  • a particular group of exemplary haloCi- 4 alkyl include methyl and ethyl groups substituted with one to three halo atoms, in particular one to three fluoro atoms, such as trifluoromethyl or 2,2,2-trifluoroethyl.
  • 'haloCi- 4 alkoxy' as used herein, includes straight chain, branched chain or cyclic alkoxy groups containing 1 to 4 carbon atoms substituted by one or more halo atoms, for example fluoromethoxy, difluoromethoxy and trifluoromethoxy.
  • a particular group of exemplary haloCi- 4 alkyl include methoxy and ethoxy groups substituted with one to three halo atoms, in particular one to three fluoro atoms.
  • the term '5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom' includes for example dihydrofuran, dihydropyran, furan, pyran, oxazole, isoxazole, oxazine, dioxine, morpholine or 1,3-dioxalane.
  • the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge et al., 1977. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g.
  • organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • Other salts e.g. oxalates or formates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.
  • Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g. as the hydrate.
  • This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water).
  • the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) for use in the prophylaxis or treatment of pain, a method of prophylaxis or treatment of pain by administering a derivative of a compound of formula (I), and the use of a derivative of a compound of formula (I) in the manufacture of a medicament for the prophylaxis or treatment of pain.
  • pharmaceutically acceptable derivative includes any pharmaceutically acceptable prodrug such as an ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
  • a pharmaceutically acceptable prodrug is formed by functionalising the secondary nitrogen of the hydantoin or triazolone, for example with a group "L" as illustrated in each Z group below:
  • a compound of formula (I) may be functionalised via the secondary nitrogen of the hydantoin or triazolone with a group L, wherein L is selected from :
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as 2 H (deuterium), 3 H, C, 13 C, 14 C, 18 F, 123 l or 125 l, which may be naturally occurring or non-naturally occurring isotopes. Unless isotopic enrichment is required, suitably the isotope content of the compound of formula (I) is not altered from that commonly found in nature.
  • Tritiated, i.e. 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • C and 18 F isotopes are particularly useful in PET (positron emission tomography).
  • the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
  • the compounds of formula (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth below, those in the Examples, and modifications thereof.
  • Compounds of formula (I), and salts and solvates thereof wherein W is group (Wa) may be prepared by the general methods outlined in WO2012/168710.
  • Compounds of formula (I), and salts and solvates thereof wherein W is group (Wb) may be prepared by the general methods outlined in WO2012/076877.
  • the present invention provides a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels for use in the prophylaxis or treatment of pain wherein the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels is a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, as defined above.
  • the present invention further provides the use of a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels in the manufacture of a medicament for the prophylaxis or treatment of pain wherein the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels is a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, as defined above.
  • the present invention also provides a method of prophylaxis or treatment of pain by administering a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels wherein the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels is a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, as defined above.
  • a 'modulator' as used herein refers to a compound which is capable of producing at least 20% potentiation of whole-cell currents mediated by human Kv3.1 and/or human Kv3.2 and/or human Kv3.3 channels recombinantly expressed in mammalian cells.
  • Compounds of the invention may be tested in an assay such as provided in Example 1 to determine their modulatory properties.
  • the modulator is capable of producing at least 20% potentiation of whole- cell currents mediated by human Kv3.1 channels recombinantly expressed in mammalian cells.
  • the pECso of the modulator is in the range of 4-7 (such as 5-6.5).
  • the modulator is capable of producing at least 20% potentiation of whole- cell currents mediated by human Kv3.2 channels recombinantly expressed in mammalian cells.
  • the pECso of the modulator is in the range of 4-7 (such as 5-6.5).
  • the modulator is capable of producing at least 20% potentiation of whole- cell currents mediated by human Kv3.3 channels recombinantly expressed in mammalian cells.
  • the pECso of the modulator is in the range of 4-7 (such as 5-6.5).
  • the modulator is capable of producing at least 20% potentiation of whole-cell currents mediated by human Kv3.1 and Kv3.2 channels recombinantly expressed in mammalian cells.
  • the modulator is capable of producing at least 20% potentiation of whole-cell currents mediated by human Kv3.1 and Kv3.3 channels recombinantly expressed in mammalian cells.
  • the modulator is capable of producing at least 20% potentiation of whole-cell currents mediated by human Kv3.2 and Kv3.3 channels recombinantly expressed in mammalian cells.
  • the modulator is capable of producing at least 20% potentiation of whole-cell currents mediated by human Kv3.1, Kv3.2 and Kv3.3 channels recombinantly expressed in mammalian cells.
  • the modulator (such as the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative) is selective for modulation of Kv3.1 channels over modulation of Kv3.2 channels.
  • selective it is meant that the modulator demonstrates, for example, at least a 2 fold, 5 fold or 10 fold activity for Kv3.1 channels than for Kv3.2 channels.
  • the activity of a modulator is suitably quantified by its potency as indicated by an EC50 value.
  • the modulator (such as a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative) is selective for modulation of Kv3.2 channels over modulation of Kv3.1 channels.
  • the modulator demonstrates, for example at least a 2 fold, 5 fold or 10 fold activity for Kv3.2 channels than for Kv3.1 channels.
  • Example 15 disclosed in WO2013/175215 is a compound of the invention which demonstrates selectivity for Kv3.2 channels.
  • the modulator (such as the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative) is selective for modulation of Kv3.1 channels over modulation of Kv3.3 channels.
  • selective it is meant that the modulator demonstrates, for example, at least a 2 fold, 5 fold or 10 fold activity for Kv3.1 channels than for Kv3.3 channels.
  • the activity of a modulator is suitably quantified by its potency as indicated by an EC50 value.
  • the modulator (such as a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative) is selective for modulation of Kv3.3 channels over modulation of Kv3.1 channels.
  • the modulator demonstrates, for example at least a 2 fold, 5 fold or 10 fold activity for Kv3.3 channels than for Kv3.1 channels.
  • the activity of a modulator is suitably quantified by its potency as indicated by an EC50 value.
  • the modulator (such as the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative) is selective for modulation of Kv3.2 channels over modulation of Kv3.3 channels.
  • the modulator demonstrates, for example, at least a 2 fold, 5 fold or 10 fold activity for Kv3.2 channels than for Kv3.3 channels.
  • the activity of a modulator is suitably quantified by its potency as indicated by an EC50 value.
  • the modulator (such as a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative) is selective for modulation of Kv3.3 channels over modulation of Kv3.2 channels.
  • the modulator demonstrates, for example at least a 2 fold, 5 fold or 10 fold activity for Kv3.3 channels than for Kv3.2 channels.
  • the activity of a modulator is suitably quantified by its potency as indicated by an EC50 value.
  • the modulator (such as a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative) demonstrates
  • Compound 3 is a compound of the invention which demonstrates a comparable activity between modulation of Kv3.1 and Kv3.2 channels.
  • the activity of a modulator is suitably quantified by its potency as indicated by an EC50 value.
  • the modulator (such as a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative) demonstrates
  • the activity for one channel is less than 2 fold that for the other channel, such as less than 1.5 fold or less than 1.2 fold.
  • the activity of a modulator is suitably quantified by its potency as indicated by an EC50 value.
  • the modulator (such as a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative) demonstrates
  • the activity for one channel is less than 2 fold that for the other channel, such as less than 1.5 fold or less than 1.2 fold.
  • the activity of a modulator is suitably quantified by its potency as indicated by an EC50 value.
  • the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 is selective over other channels which have been associated with pain.
  • the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 is capable of providing an increase of whole-cell currents of, on average, at least 20% of the increase observed with 50 micromolar /V-cyclohexyl-/V-[(7,8-dimethyl-2-oxo- l,2-dihydro-3-quinolinyl)methyl]-/V'-phenylurea
  • the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 does not have a notable effect on Kv3.4, Kv7.2/7.3, and/or Nav 1.7 currents.
  • the Examples herein provide suitable methods for the testing of Kv3.1, Kv3.2, Kv3.3, Kv 3.4, Kv7.2/7.3, and Nav 1.7 currents.
  • the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 is selective over Kv3.4.
  • the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 is capable of providing an increase of Kv3.1 and/or Kv3.2 and/or Kv3.3 whole-cell currents of, on average, at least 20% of the increase observed with 50 micromolar /V-cyclohexyl-/V-[(7,8-dimethyl-2-oxo-l,2-dihydro-3- quinolinyl)methyl]-/V'-phenylurea but provides an increase of less than 10% (such as less than 5%, especially less than 1% or suitably no increase) in Kv3.4 current at the same concentration (e.g. 10 uM).
  • the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 is selective over
  • the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 is capable of providing an increase of Kv3.1 and/or Kv3.2 and/or Kv3.3 whole-cell currents of, on average, at least 20% of the increase observed with 50 micromolar /V-cyclohexyl-/V-[(7,8-dimethyl-2-oxo-l,2- dihydro-3-quinolinyl)methyl]-/V'-phenylurea but provides an increase of less than 10% (such as less than 5%, especially less than 1% or suitably no increase) in Kv7.2/7.3 current at the same concentration (e.g. 10 uM).
  • the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 is selective over Navl.7.
  • the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 is capable of providing an increase of Kv3.1 and/or Kv3.2 and/or Kv3.3 whole-cell currents of, on average, at least 20% of the increase observed with 50 micromolar /V-cyclohexyl-/V-[(7,8-dimethyl-2-oxo-l,2-dihydro-3- quinolinyl)methyl]-/V'-phenylurea but provides an increase of less than 10% (such as less than 5%, especially less than 1% or suitably no increase) in Navl.7 current at the same
  • treatment includes the control, mitigation, reduction, or modulation of the disease state or its symptoms.
  • pain is used herein to mean preventing symptoms of a disease or disorder in a subject or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction.
  • pain that may be mediated by a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels is chronic pain.
  • pain is acute pain.
  • the pain indications that may be mediated by a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels is nociceptive, neuropathic, inflammatory or miscellaneous pain.
  • Nociceptive pain represents the normal response to noxious insult or injury of tissues such as skin, muscles, visceral organs, joints, tendons, or bones.
  • nociceptive pain which form part of the invention include somatic pain: musculoskeletal (joint pain, myofascial pain) or cutaneous, which is often well localized; or visceral pain: hollow organs or smooth muscle.
  • Neuropathic pain is pain initiated or caused by a primary lesion or disease in the somatosensory nervous system. Sensory abnormalities range from deficits perceived as paraesthesia (numbness) to hypersensitivity (hyperalgesia or allodynia), and dysaesthesia (tingling and other sensations).
  • neuropathic pain which form part of the invention include, but are not limited to, diabetic neuropathy, post-herpetic neuralgia, spinal cord injury pain, phantom limb (post-amputation) pain, and post-stroke central pain.
  • Other causes of neuropathic pain include trauma, chemotherapy and heavy metal exposure.
  • Inflammatory pain occurs as a result of activation and sensitization of the nociceptive pain pathway by a variety of mediators released at a site of tissue inflammation.
  • cytokines such as IL-l-alpha, IL-l-beta, IL-6 and TNF-alpha
  • chemokines reactive oxygen species, vasoactive amines, lipids, ATP, acid, and other factors released by infiltrating leukocytes, vascular endothelial cells, or tissue resident mast cells.
  • Examples causes of inflammatory pain which form part of the invention include appendicitis, rheumatoid arthritis, inflammatory bowel disease, and herpes zoster.
  • Miscellaneous pain refers to pain conditions or disorders which are not easily classifiable.
  • the current understanding of their underlying mechanisms is still rudimentary though specific therapies for those disorders are well known; they include cancer pain, migraine and other primary headaches and wide-spread pain of the fibromyalgia type.
  • specific pain indications that may be mediated by a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels are neuropathic pain and/or inflammatory pain.
  • the neuropathic pain that may be ameliorated by a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels may be central or peripheral neuropathic pain.
  • Central neuropathic pain is caused by damage to or dysfunction of the central nervous system (CNS), which includes but is not limited to the brain, brainstem, and spinal cord.
  • Peripheral neuropathic pain is caused by damage to or dysfunction of the peripheral nervous system, which includes but is not limited to sensory nerves, motor nerves and autonomic nerves.
  • the neuropathic pain is central neuropathic pain.
  • the neuropathic pain is peripheral neuropathic pain.
  • Pain is a subjective condition and in a clinical setting tends to be measured by a patient's self- assessment. Therefore, it can be difficult to measure and quantify pain threshold.
  • a subjective 11-point rating scale is used where 0 is no pain and 10 is the worst pain imaginable.
  • Subjects generally record their worst pain over a given period, usually a day.
  • a minimum mean baseline score is also recorded and response to the medication is measured relative to the baseline, for example, a reduction of at least 10%, 20%, 30%, 40% or 50% in pain from the baseline score may be observed.
  • a reduction of at least 10%, 20%, 30%, 40% or 50% in pain from the baseline score is observed upon administration of a Kv3.1/Kv3.2/Kv3.3 modulator, such as a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof to a subject in need thereof.
  • a Kv3.1/Kv3.2/Kv3.3 modulator such as a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof
  • a Kv3.1/Kv3.2/Kv3.3 modulator can occur before an anticipated onset of pain or after the onset of pain. In cases where it is anticipated that development of a disease or disorder may lead to an increase in pain experienced by the subject, a Kv3.1/Kv3.2/Kv3.3 modulator, such as a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof can be administered. In cases where a subject is already
  • a Kv3.1/Kv3.2/Kv3.3 modulator such as a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may be administered to a subject in need thereof.
  • Treatment of the subject in need thereof may continue for as long as treatment is required, for example, 1 day, 1 week, 2 weeks, 3 weeks, 1 month, 6 months, 1 year, more than 1 year more than 2 years, more than 5 years or more than 10 years. Therefore in one embodiment of the invention, a therapeutically effective amount of a Kv3.1/Kv3.2/Kv3.3 modulator, such as a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof, is administered to a subject in need thereof for 1 day to 1 month, 1 week to 3 months, 1 month to 6 months, 3 months to 1 year or more than 1 year.
  • a Kv3.1/Kv3.2/Kv3.3 modulator such as a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof
  • Reduction in pain in a subject can be measured by assessing the response to an external stimuli such as mechanical or thermal (e.g. cold) stimuli (such as described in the Experimental section).
  • the reduction can either be considered as a percentage reversal (calculated by measuring the pre- and post-dose thresholds of the affected pain site with a non-affected pain site, such as described in more detail under Data Analysis in the Experimental Section) or by measuring withdrawal thresholds of the affected pain site.
  • the percentage reversal calculation is used.
  • the sensitivity to pain (such as neuropathic pain or inflammatory pain) is reversed by more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80% or more than 90%, upon administration of a therapeutically effective amount of a Kv3.1/Kv3.2/Kv3.3 modulator, such as a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof.
  • a Kv3.1/Kv3.2/Kv3.3 modulator such as a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof.
  • the sensitivity to pain is reversed by more than 80% or more than 90%.
  • Subjects receiving the Kv3.1/Kv3.2/Kv3.3 modulator may experience secondary benefits, such as one or more of improved function, mood, sleep, quality of life, reduced time off work.
  • the prophylaxis or treatment of pain does not include the prophylaxis or treatment of sleep disorder due to neuropathic pain.
  • the prophylaxis or treatment of pain does not include the prophylaxis or treatment of sleep disorder due to pain.
  • the modulators are usually administered as a pharmaceutical composition.
  • the invention also provides a pharmaceutical composition comprising a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 (such as a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate and/or derivative thereof), and a pharmaceutically acceptable carrier.
  • the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical compositions adapted accordingly.
  • a modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 which are active when given orally can be formulated as liquids or solids, e.g. as syrups, suspensions, emulsions, tablets, capsules or lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the active ingredient in a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • suitable pharmaceutical carrier(s) e.g. aqueous gums, celluloses, silicates or oils
  • Typical parenteral compositions consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • compositions suitable for transdermal administration include ointments, gels and patches.
  • the composition is in unit dose form such as a tablet, capsule or ampoule.
  • the composition may contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration.
  • the composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration.
  • the composition may contain from 0.05mg to lOOOmg, for example from l.Omg to 500mg, of the active material, depending on the method of administration.
  • the composition may contain from 50 mg to 1000 mg, for example from lOOmg to 400mg of the carrier, depending on the method of administration.
  • the dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 500mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
  • the modulator of Kv3.1 and/or Kv3.2 and/or Kv3.3 is used in combination with a further therapeutic agent or agents.
  • the modulators are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route. Alternatively, the compounds may be administered separately.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation. However, the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined
  • compositions may also be administered separately, through the same or different routes.
  • Therapeutic agents which may be used in combination with the present invention include NSAIDS (such as aspirin, naproxen, ibuprofen, parecoxib, diclofenac), paracetamol, pregabalin, gabapentin or opioids (such as fentanyl, sufentanil, oxycodone, morphine, tramadol, codeine).
  • NSAIDS such as aspirin, naproxen, ibuprofen, parecoxib, diclofenac
  • paracetamol such as aspirin, naproxen, ibuprofen, parecoxib, diclofenac
  • pregabalin gabapentin
  • opioids such as fentanyl, sufentanil, oxycodone, morphine, tramadol, codeine
  • Therapeutic agents which may be used in combination for neuropathic pain include pregabalin, duloxetine and capsaicin.
  • Kv3.1/Kv3.2/Kv3.3 modulator such as a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof will suitably be administered at a dosage level which achieves the desired medical outcome without undue adverse effects - namely a safe and effective dose.
  • Example dosages may be in the range of lOmg to 3g per day, such as 200mg to 1.5g per day.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • the ability of the compounds of the invention to modulate the voltage-gated potassium channel subtypes Kv3.3/Kv3.2/Kv3.1 may be determined using the following assay. Analogous methods may be used to investigate the ability of the compounds of the invention to modulate other channel subtypes.
  • a stable cell line expressing human Kv3.3 channels was created by transfecting Chinese Hamster Ovary (CHO)-Kl cells with a pBacMire_KCNC-3 vector.
  • Cells were cultured in DMEM/F12 (Gibco) supplemented with 10% Foetal Bovine Serum (Gibco), IX non-essential amino acids (Invitrogen) and geneticin (G418) 400 microg/mL. Cells were grown and maintained at 37°C in a humidified environment containing 5% C0 2 in air.
  • hKv3.2 a stable cell line expressing human Kv3.2 channels (hKv3.2) was created by transfecting CHO-K1 cells with a pCIH5-hKv3.2 vector.
  • Cells were cultured in DMEM/F12 medium supplemented by 10% Foetal Bovine Serum, IX non-essential amino acids (Invitrogen) and lOOug/ml of Hygromycin-B (Invitrogen). Cells were grown and maintained at 37°C in a humidified environment containing 5% C0 2 in air.
  • CHO/Gam/ElA-clone22 alias CGE22 cells were transduced using a hKv3.1 BacMam reagent.
  • This cell line was designed to be an improved CHO-Kl-based host for enhanced recombinant protein expression as compared to wild type CHO-K1.
  • the cell line was generated following the transduction of CHO-K1 cells with a BacMam virus expressing the Adenovirus-Gaml protein and selection with Geneticin- G418, to generate a stable cell line, CHO/Gam-A3.
  • CHO/Gam-A3 cells were transfected with pCDNA3-ElA-Hygro, followed by hygromycin-B selection and FACS sorting to obtain single-cell clones.
  • BacMam-Luciferase and BacMam-GFP viruses were then used in transient transduction studies to select the clone based on highest BacMam transduction and recombinant protein expression.
  • CGE22 cells were cultured in the same medium used for the hKv3.2 CHO-K1 stable cell line with the addition of 300ug/ml hygromycin-B and 300ug/ml G418. All other conditions were identical to those for hKv3.2 CHO-K1 cells. The day before an experiment 10 million CGE22 cells were plated in a T175 culture flask and the hKv3.1 BacMam reagent
  • Leak subtraction was conducted in all experiments by applying 50 ms hyperpolarizing (10 mV) prepulses to evoke leak currents followed by a 20 ms period at the holding potential before test pulses.
  • 50 ms hyperpolarizing (10 mV) prepulses to evoke leak currents followed by a 20 ms period at the holding potential before test pulses.
  • a first test pulse to -15 mV was applied for 100 ms and following a further 100 ms at -70 mV, a second pulse to 40 mV was applied for 50 ms.
  • Cells were then maintained for a further 100 ms at -100 mV and then a voltage ramp from -100 mV to 40 mV was applied over 200 ms.
  • a first test pulse to 0 mV was applied for 500 ms and following a further 100 ms at -70 mV, a second pulse to 40 mV was applied for 200 ms. These longer test pulses were used to study inactivation of hKv3.3 channels.
  • Test pulses protocol may be performed in the absence (pre-read) and presence (post-read) of the test compound. Pre- and post-reads may be separated by the compound addition followed by a 3-minute incubation. Solutions and drugs
  • the intracellular solution contained the following (in mM): K-gluconate 100, KCI 54, MgCI 2 3.2, HEPES 5, adjusted to pH 7.3 with KOH.
  • Amphotericin-B solution was prepared as 50mg/ml stock solution in DMSO and diluted to a final working concentration of 0.1 mg/ml in intracellular solution.
  • the external solution was Dulbecco's Phosphate Buffered Saline (DPBS) and contained the following (in mM): CaCI 2 0.90, KCI 2.67, KH 2 P0 4 1.47, MgCI.6H 2 0 0.493, NaCI 136.9, Na 3 P0 4 8.06, with a pH of 7.4.
  • DMSO dimethylsulfoxide
  • the recordings were analysed and filtered using both seal resistance (>20 ⁇ ) and peak current amplitude (>500pA at the voltage step of 40 mV) in the absence of compound to eliminate unsuitable cells from further analysis.
  • seal resistance >20 ⁇
  • peak current amplitude >500pA at the voltage step of 40 mV
  • paired comparisons of evoked currents between pre- and post-drug additions measured for the -15 mV voltage step were used to determine the positive modulation effect of each compound.
  • Kv3 channel-mediated outward currents were measured determined from the mean amplitude of the current over the final 10ms of the -15mV voltage pulse minus the mean baseline current at -70mV over a 10ms period just prior to the -15mV step.
  • Kv3 channel currents following addition of the test compound were then compared with the currents recorded prior to compound addition.
  • Data were normalised to the maximum effect of the reference compound (50microM of /V-cyclohexyl-/V-[(7,8-dimethyl-2-oxo-l,2-dihydro-3- quinolinyl)methyl]-/V'-phenylurea) and to the effect of a vehicle control (0.5% DMSO).
  • the normalised data were analysed using ActivityBase or Excel software.
  • the concentration of compound required to increase currents by 50% of the maximum increase produced by the reference compound (EC50) was determined by fitting of the concentration-response data using a four parameter logistic function in ActivityBase.
  • paired comparisons of evoked currents between pre- and post-drug additions were measured for the OmV step, considering the peak current and the decay (inactivation) of the current over the duration of the Omv test pulse (500ms).
  • Kv3.1 and/or Kv3.2 positive modulators produce in the above assay an increase of whole-cell currents of, on average, at least 20% of the increase observed with 50 micromolar /V-cyclohexyl-/V-[(7,8-dimethyl-2-oxo-l,2-dihydro-3- quinolinyl)methyl]-/V'-phenylurea.
  • Compound 1 was found to have a pEC50 for Kv3.3 of 5.17.
  • Compound 2 was found to have a pEC50 for Kv3.3 of 4.93.
  • Compound 3 was found to have a pEC50 for Kv3.3 of 4.76.
  • a secondary analysis of the data from the hKv3.1, hKv3.2 and hKv3.3 assays described in Example 1 may be used to investigate the effect of the compounds on rate of rise of the current from the start of the depolarising voltage pulses.
  • the magnitude of the effect of a compound can be determined from the time constant (Tau ac t) obtained from a non-linear fit, using the equation given below, of the rise in Kv3.1, Kv3.2 and Kv3.3 currents following the start of the -15mV depolarising voltage pulse.
  • Y0 is the current value at the start of the depolarising voltage pulse
  • Ymax is the plateau current
  • K is the rate constant
  • Tau ac t is the activation time constant, which is the reciprocal of K.
  • the effect of the compounds on the time taken for Kv3.1, Kv3.2 or Kv3.3 currents to decay on closing of the channels at the end of the -15mV depolarising voltage pulses can also be investigated.
  • the magnitude of the effect of a compound on channel closing can be determined from the time constant (Ta udeact) of a non-linear fit of the decay of the current ("tail current") immediately following the end of the depolarising voltage pulse.
  • Kv3.1, Kv3.2 and Kv3.3 channels must activate and deactivate very rapidly in order to allow neurons to fire actions potentials at high frequency (Rudy et al., 2001). Slowing of activation is likely to delay the onset of action potential repolarisation; slowing of deactivation could lead to hyperpolarising currents that reduce the excitability of the neuron and delay the time before the neuron can fire a further action potential. Together these two slowing effects on channel activation and deactivation are likely to lead to a reduction rather than a facilitation of the neurons ability to fire at high frequencies.
  • Example 2 Evaluation of the effect of modulators of Kv3.1/Kv3.2 channels on sensitivity to mechanical and cold stimuli in models of neuropathic and inflammatory pain in the rat
  • Subjects comprised male, Wistar Hanover rats, 6 animals per group (225 ⁇ 2g for Compound 1 studies and Compound 2 studies; 214 ⁇ lg for Compound 3 studies; 236 ⁇ lg for Compound 4 studies).
  • intraperitoneal route was prepared using autoclaved deionized water not more than one week prior to use.
  • Table 1 Dosing regimen for neuropathic and inflammatory pain models.
  • the control for the neuropathic pain model was lamotrigine, administered at 30 mg/kg via oral delivery.
  • the control for the inflammatory pain model was diclofenac, administered at 30 mg/kg via oral delivery.
  • Statistical analysis was performed using one-way ANOVA, and comparisons were performed with time-matched vehicle group using Tukey's HSD test wherein * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001.
  • Neuropathic pain was induced by partial ligation of the sciatic nerve. Briefly, the rats were anaesthetised (isoflurane/02 inhalation), the left sciatic nerve exposed at mid-thigh level through a small incision and 1/3 to 1/2 of the nerve thickness tightly ligated within a 7.0 silk suture. The wound was closed with surgical glue. Animals were allowed to recover and tested 12-15 days following surgery. Withdrawal thresholds or latencies were measured on both the ipsilateral (ligated) and contralateral (non-ligated) paws, prior to (predose) and then up to 24 h following drug or vehicle administration.
  • Pre-dose behavioural measurements were obtained by measuring paw withdrawals 14 days following nerve ligation; before the initiation of drug treatment. Following treatment, further readings were taken at 1, 3, 6 and 24 hour after administration.
  • the hyperalgesia was induced by an intraplantar injection (25 ⁇ ) of Freund's Complete Adjuvant (FCA) into the left hind paw.
  • FCA Freund's Complete Adjuvant
  • paw withdrawal thresholds or latencies were measured on both the ipsilateral (FCA-injected) and contralateral (non-injected) paws, prior to (naive) and 24 hours following FCA injection (predose), and then at 1, 3, 6 and 24 hours after drug or vehicle administration.
  • the animals were lightly restrained and each hind paw in turn placed onto the surface of the cold-plate. The end point was taken as the withdrawal of the paw and recorded as the withdrawal latency for the ipsilateral and the contralateral paw. A maximum cut-off of 30 seconds was used for each paw.
  • Partial ligation of the sciatic nerve resulted in a marked decrease in withdrawal threshold to a mechanical stimulus and in withdrawal latency to a cold stimulus of the affected paw.
  • Peak reversal of mechanical sensitivity was seen at 3 hours post-dose (51% at 30mg/kg and 68% by 60mg/kg). Cold sensitivity was reversed at 3 hours post-dose by 52% and 125% by 30 mg/kg and 60mg/kg respectively.
  • the lower dose of the compound was only statistically active against mechanical hyperalgesia. At 60mg/kg the compound was still efficacious at 6 hours post-dose.
  • the positive control, lamotrigine gave peak reversals of 65% (at 3 hours post-dose) and 58% (at 1 hour post-dose) in mechanical and cold respectively.
  • Partial ligation of the sciatic nerve resulted in a marked decrease in withdrawal threshold to a mechanical stimulus and in withdrawal latency to a cold stimulus of the affected paw.
  • Compound 1 produced a dose-related reversal of mechanical (Fig.3a, Fig.3c) and cold sensitivity (Fig.4a, Fig.4c) with rapid onset and long duration of action.
  • Peak reversal of mechanical sensitivity was seen at 3 hours post-dose (31% at lOmg/kg, 73% at 30mg/kg and 81% by 60mg/kg).
  • Cold sensitivity was reversed at 3 hours post-dose by 39%, 68% and 76% by 10, 30 and 60mg/kg respectively.
  • the positive control, lamotrigine gave peak reversals at 3 hours post-dose of 67% and 67% in mechanical and cold respectively.
  • the intraplantar injection of FCA resulted in a marked decrease in withdrawal threshold to a mechanical stimulus and in withdrawal latency to a cold stimulus of the affected paw.
  • the mean naive threshold readings were 105 ⁇ lg.
  • predose threshold readings of 65 ⁇ l.Og were measured in the ipsilateral paws compared to 104 ⁇ l.Og in the contralateral paws (Fig.5a, Fig.5b).
  • the mean naive cold latency readings were 11.8 ⁇ 0.2s.
  • predose threshold readings of 7.3 ⁇ 0.1s were measured in the ipsilateral paws compared to 11.5 ⁇ 0.2s in the contralateral paws (Fig.6a, Fig.6b).
  • Compound 1 produced a dose-related reversal of both mechanical (Fig.5a, Fig.5c) and cold sensitivity (Fig.6a, Fig.6b) with rapid onset of action and peak reversal at 1-3 h post-dose. Peak reversal of mechanical sensitivity was seen at 1 hour post-dose for 30mg/kg and 60mg/kg (74% and 92% respectively) and at 3 hours post-dose for lOmg/kg (64% reversal). Peak reversal of cold sensitivity was seen at 3 hours post-dose for lOmg/kg and 30mg/kg (45% and 65% respectively) and at 1 hour post-dose for 60mg/kg (92% reversal).
  • Partial ligation of the sciatic nerve resulted in a marked decrease in withdrawal threshold to a mechanical stimulus and in withdrawal latency to a cold stimulus of the affected paw.
  • Compound 2 produced a reversal of both mechanical (Fig.7a, Fig.7c) and cold sensitivity (Fig.8a, Fig.8c) with rapid onset of action and efficacy similar to lamotrigine. There was little difference in efficacy between the 2 doses of the compound. Peak reversal of mechanical sensitivity was seen at 1 hour post-dose (53% at 30mg/kg and 47% by 60mg/kg). Cold sensitivity was reversed at 1 hour post-dose by 42% and 71% by 30mg/kg and 60mg/kg respectively, although peak reversal was observed at 3 hours post-dose for 30 mg/kg (55% reversal). Both doses of the compound were efficacious at 3 hours by not by 6 hours post- dose. The positive control, lamotrigine, gave peak reversals at 3 hours post-dose of 54% and 58% in mechanical and cold respectively. There were no apparent behavioural changes in the rats.
  • Partial ligation of the sciatic nerve resulted in a marked decrease in withdrawal threshold to a mechanical stimulus and in withdrawal latency to a cold stimulus of the affected paw.
  • Compound 2 produced a dose-related reversal of mechanical (Fig.9a, Fig.9c) and cold sensitivity (Fig.10a, Fig.10c) with rapid onset of action. Peak reversal of mechanical sensitivity was seen at 3 hours post-dose (31% at lOmg/kg, 72% at 30mg/kg and 81% by 60mg/kg). Cold sensitivity was reversed at 3 hours post-dose by 35%, 70% and 95% by 10, 30 and 60mg/kg respectively. The positive control, lamotrigine, gave peak reversals at 3 hours post-dose of 67% and 67% in mechanical and cold respectively. There were small changes in contralateral paw withdrawals and latencies with Compound 2 which just attained significance at 3 hours on mechanical.
  • the intraplantar injection of FCA resulted in a marked decrease in withdrawal threshold to a mechanical stimulus and in withdrawal latency to a cold stimulus of the affected paw.
  • the mean naive threshold readings were 106 ⁇ lg. Twenty-four hours after FCA injection, predose threshold readings of 67 ⁇ l.Og were measured in the ipsilateral paws compared to 106 ⁇ l.Og in the contralateral paws (Fig.11a, Fig. lib).
  • the mean naive cold latency readings were 11.1 ⁇ 0.2s.
  • Peak reversal of mechanical sensitivity was seen at 3 hours post-dose (46% at 10 mg/kg and 67% at 60mg/kg). Peak reversal of cold sensitivity was seen at 1 hour post-dose (96% with 60mg/kg), and seen at 3 hours post-dose for 30 mg/kg (58% reversal). At 3 hours post-dose, the compound was still efficacious at 60 mg/kg (81% reversal). The cold sensitivity was particularly good in this study. Following FCA at 24h the paw swelling often results in variable cold withdrawal latencies. Here, although more variable than the mechanical readouts, there were fairly consistent withdrawals latencies to cold.
  • Partial ligation of the sciatic nerve resulted in a marked decrease in withdrawal threshold to a mechanical stimulus and in withdrawal latency to a cold stimulus of the affected paw.
  • Compound 3 produced a dose-related reversal of both mechanical (Fig.13a, Fig.13c) and cold sensitivity (Fig.14a, Fig.14c) with slow onset of action.
  • FCA The intraplantar injection of FCA resulted in a marked decrease in withdrawal threshold to a mechanical stimulus and in withdrawal latency to a cold stimulus of the affected paw.
  • example Compound 3 produced a reversal of either mechanical (Fig.15a, Fig.15c) or cold sensitivity (Fig.16a, Fig.16c).
  • the compound had a slow onset of action, with little reversal evident at 1 hour post-dose. Peak reversal was seen at 3 h post-dose for both mechanical and cold sensitivity after which it declined but activity still evident at 6 hours post- dose (significant on mechanical thresholds).
  • the intraplantar injection of FCA resulted in a marked decrease in withdrawal threshold to a mechanical stimulus and in withdrawal latency to a cold stimulus of the affected paw.
  • the mean naive threshold readings were 104 ⁇ lg. Twenty-four hours after FCA injection, predose threshold readings of 64 ⁇ l.Og were measured in the ipsilateral paws compared to 104 ⁇ l.Og in the contralateral paws (Fig.17a, Fig 17b).
  • the mean naive cold latency readings were 11.1 ⁇ 0.1s.
  • Example 3 Specificity of compounds as potentiators of Kv3.1 and/or 3.2 and/or 3.3 To confirm that the utility of Compounds 1, 2, 3 and 4 derives from their ability to potentiate Kv3.1 and/or 3.2 and/or 3.3 channel activity, the ability of the compounds to potentiate other pain associated targets was investigated.
  • intracellular solution was loaded into the intracellular compartments of the QPIate and cell suspension was pipetted into the extracellular compartments.
  • membrane currents were recorded using up to 48 parallel patch clamp amplifiers in the QPatch HT ® system. The current records were sampled at 2000 Hz and low-pass Bessel filtered at 400 Hz.
  • Human Kv3.4 channels were stably expressed in a HEK293 cell line.
  • Cells were used within 1-4 hours of cell preparation and internal and external physiological solutions were freshly prepared prior to the assay. Electrophysiological recordings were made using an automated patch clamp platform (QPatch, Sophion Biosciences).
  • the extracellular solution contained 145 mM NaCI, 4 mM KCI, 2mM CaCI 2 , 1 mM MgCI 2 , 10 mM HEPES and 10 mM glucose; the pH was adjusted to 7.4 with NaOH, and the osmolarity measured as 313 mOsm/L.
  • a low potassium intracellular solution which contained 135.6 mM CsCI, 5.37 mM CaCI 2 , 1.75 mM MgCI 2 , 10 mM EGTA, 15.6 mM KOH, 4 mM Na 2 ATP and 10 mM HEPES; the pH was adjusted to 7.2 with CsOH, and the osmolarity measured as 303 mOsm/L.
  • the time constants of the inactivation phase of the hKv3.4 currents were derived from a mono ( ⁇ ) or a double ( ⁇ and ⁇ 2 ) standard exponential fit to peak trace pulse from -80mV to +60mV.
  • the time-course of effect of the compounds against the hKv3.4 potassium channel was measured with repetitive voltage pulses from a holding potential of -60mV, with pulses of 500ms duration every 5s to +40mV.
  • test compounds concentration (10 uM) of the test compounds was assessed during the activation, inactivation and peak pulse protocols. The protocol was applied with addition of physiological solution (control period), followed by 10 uM of the testing compound and a 10 mM of the standard blocker TEA.
  • hKv3.4 channels were heterologously expressed in Xenopus ooctyes following microinjection of in vitro transcribed mRNA (mMessage mMachine kit, Ambion, Austin, TX).
  • Whole-oocyte currents were recorded 1-4 day post-microinjection at room temperature (21-23°C) under two-electrode voltage-clamp conditions (OC-725C, Warner, Hamden, CT).
  • ND-96 and ND-96 plus the test compound were delivered using a gravity-driven perfusion system.
  • Concentration of 0.1% DMSO did not lead to significant effects on the amplitude of the fully activated peak of the hKv7.2/7.3 channel, which generally remain stable for the duration of a typical whole-cell recording.
  • Perfusion of the test compounds was started if cells had less than 10% run-down within a two full l-V control protocols. Cells with higher run-down were excluded from further analysis.
  • agonist retigabine from Alomone Labs, Israel
  • blocker TEA from Sigma
  • Human Navl.7 channels were stably expressed in a HEK293 cell line. Electrophysiological recordings were made at room temperature using an automated patch clamp platform (QPatch, Sophion Biosciences).
  • the QPatch assay was carried out at room temperature using the QPatch platform (Sophion). On the day of the experiment cells were cultured according to standard cell preparation for QPatch. Internal and external physiological solutions were freshly prepared prior to the assay.
  • the standard extracellular solution contained 145mM NaCI, 4mM KCI, 2mM CaCI 2 , 2mM MgCI 2 , lOmM HEPES and lOmM glucose; the pH was adjusted to 7.4 with NaOH, and the osmolarity measured as 314mOsm/L.
  • the standard intracellular solution contained 140mM CsF, lOmM NaCI, 5mM CsOH, ImM EGTA, lOmM HEPES; the pH was adjusted to 7.25 with CsOH, and the osmolarity measured as 293mOsm/L.
  • a series of 40 voltage pulses (from -120mV to OmV, 2.4 ms long at 117Hz) were applied every 60s in control (twice), compound (five times), standard blocker (twice) and washout (twice).
  • the % inhibition values were calculated by normalising the data relative to the 1st pulse (PI) and by calculating the ratio between the 40th pulse versus the 1st pulse (P40/1). Series resistance and quality of seals were monitored during the experiments. Sophion QPatch Assay Software 5.0 was used to analyse and plot all the graphs. 10 ⁇ of the test compound was applied followed by ⁇ TTX (standard blocker), followed by saline (washout).
  • Seizure Beget Seizure The Quest for GABA as a Key Player. Crit. Rev. Neurobiol. 2006;18(1-2):135-144.
  • Fisahn A Kainate receptors and rhythmic activity in neuronal networks: hippocampal gamma oscillations as a tool. J. Physiol. 2005 Oct;561(l):65-72.

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EP16813020.1A EP3386506B1 (en) 2015-12-10 2016-12-09 Modulators of kv3 channels to treat pain
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CA3005302A CA3005302A1 (en) 2015-12-10 2016-12-09 Modulators of kv3 channels to treat pain
BR112018011700-5A BR112018011700B1 (pt) 2015-12-10 2016-12-09 Moduladores de canais de kv3 para tratar dor
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FIEP16813020.1T FI3386506T3 (fi) 2015-12-10 2016-12-09 Kv3-kanavien modulaattoreita kivun hoitamiseksi
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KR1020187017088A KR20180097549A (ko) 2015-12-10 2016-12-09 통증을 치료하기 위한 kv3 채널의 조절제
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WO2018220762A1 (ja) * 2017-05-31 2018-12-06 大塚製薬株式会社 ピリミジン化合物
WO2020079422A1 (en) 2018-10-16 2020-04-23 Autifony Therapeutics Limited Novel compounds
WO2020089262A1 (en) * 2018-10-30 2020-05-07 H. Lundbeck A/S Arylsulfonylpyrolecarboxamide derivatives as kv3 potassium channel activators
US10934278B2 (en) 2016-07-29 2021-03-02 Autifony Therapeutics Limited Compounds
WO2021156584A1 (en) 2020-02-06 2021-08-12 Autifony Therapeutics Limited Kv3 modulators
WO2023017263A1 (en) 2021-08-10 2023-02-16 Autifony Therapeutics Limited Potassium channel modulators
US11944623B2 (en) 2015-12-10 2024-04-02 Autifony Therapeutics Limited Modulators of Kv3 channels to treat pain
WO2024121552A1 (en) 2022-12-06 2024-06-13 Autifony Therapeutics Limited Compounds for the treatment of centra nervous system disorders

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CN113788741B (zh) * 2021-09-28 2023-12-29 大连九信精细化工有限公司 一种制备2-环丙基苯酚衍生物的方法

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US9669030B2 (en) 2012-05-22 2017-06-06 Autifony Therapeutics Limited Hydantoin derivatives as Kv3 inhibitors
WO2013182851A1 (en) 2012-06-06 2013-12-12 Autifony Therapeutics Limited Prophylaxis or treatment of diseases where a modulator of kv3.3 channels is required
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US11944623B2 (en) 2015-12-10 2024-04-02 Autifony Therapeutics Limited Modulators of Kv3 channels to treat pain
US10934278B2 (en) 2016-07-29 2021-03-02 Autifony Therapeutics Limited Compounds
WO2018109484A1 (en) 2016-12-16 2018-06-21 Autifony Therapeutics Limited Hydantoin modulators of kv3 channels
WO2018220762A1 (ja) * 2017-05-31 2018-12-06 大塚製薬株式会社 ピリミジン化合物
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TWI827706B (zh) * 2018-10-16 2024-01-01 英商奧堤凡尼治療股份有限公司 新穎化合物
WO2020089262A1 (en) * 2018-10-30 2020-05-07 H. Lundbeck A/S Arylsulfonylpyrolecarboxamide derivatives as kv3 potassium channel activators
CN113056461A (zh) * 2018-10-30 2021-06-29 H.隆德贝克有限公司 作为Kv3钾通道激活剂的芳基磺酰基吡咯甲酰胺衍生物
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WO2023017263A1 (en) 2021-08-10 2023-02-16 Autifony Therapeutics Limited Potassium channel modulators
WO2024121552A1 (en) 2022-12-06 2024-06-13 Autifony Therapeutics Limited Compounds for the treatment of centra nervous system disorders

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